US6048883A - Heterocyclic compounds as pharmaceutical - Google Patents

Heterocyclic compounds as pharmaceutical Download PDF

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US6048883A
US6048883A US08/360,755 US36075595A US6048883A US 6048883 A US6048883 A US 6048883A US 36075595 A US36075595 A US 36075595A US 6048883 A US6048883 A US 6048883A
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ethoxy
methylamino
benzoxazolyl
phenyl
formula
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David Haigh
John Thomas Sime
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority claimed from GB929214185A external-priority patent/GB9214185D0/en
Priority claimed from GB929227030A external-priority patent/GB9227030D0/en
Priority claimed from GB939311027A external-priority patent/GB9311027D0/en
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Priority to US08/460,162 priority Critical patent/US5827865A/en
Priority to US08/458,335 priority patent/US5869495A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to certain novel compounds, to a process for preparing such compounds, to pharmaceutical compositions containing such compounds and to the use of such compounds and compositions in medicine.
  • R is (C 1 -C 8 )alkyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, phenyl, (C 7 -C 8 )phenylalkyl, (C 2 -C 8 )alkanoyl, or one of said groups mono- or disubstituted with (C 1 -C 3 )alkyl, trifluoromomethyl, hydroxy, (C 1 -C 3 )alkoxy, fluoro or chloro;
  • W is O, CO, CH 2 , CHOH or --CH ⁇ CH--;
  • X is S, O, NR 2 , --CH ⁇ CH--, --CH ⁇ N-- or --N ⁇ CH--'
  • Y is CH or N
  • Z is H, amino, (C 1 -C 7 )alkyl, (C 3 -C 7 )cycloalkyl, phenyl, or phenyl mono- or disubstituted with (C 1 - 3 )alkyl, trifluoromethyl, (C 1 -C 3 )alkoxy, phenyl, phenoxy, benzyl, benzyloxy, fluoro or chloro;
  • Z 1 is hydrogen or (C 1 -C 3 )alkyl
  • X 1 is O, S, SO or SO 2 ;
  • Y 1 is hydroxy, (C 1 -C 3 )alkoxy, phenoxy, benzyloxy, amino, (C 1 -C 4 )alkanoylamino, (C 1 -C 4 )alkanesulfonyl-amino, benzenesulfonylamino, naphthalenesulfonylamino, di[(C 1 -C 3 )alkyl]aminosulfonylamino, or one of said groups mono- or disubstituted with (C 1 -C 3 )alkyl, trifluoromethyl, hydroxy, (C 1 -C 3 )alkoxy, fluoro or chloro; the pharmaceutically-acceptable cationic salts thereof when Y 1 is hydroxy; and the pharmaceutically-acceptable acid addition salts thereof when the compounds contain a basic nitrogen atom.
  • These compounds are also indicated to be of potential use for the treatment and/or prophylaxis of other diseases including hyperlipidaemia and hypertension. They are also indicated to be of use in the treatment and/or prophylaxis of cardiovascular disease, especially atherosclerosis. In addition these compounds are considered to be useful for treating certain eating disorders, in particular the regulation of appetite and food intake in subjects suffering from disorders associated with under-eating, such as anorexia nervosa, and disorders associated with over-eating, such as obesity and anorexia bulimia.
  • a 1 represents a substituted or unsubstituted aromatic heterocyclyl group
  • a 3 represents a moiety of formula --(CH 2 ) m CH(OR 1 )-- wherein R 1 represents substituted or unsubstituted alkyl, aryl, aralkyl or alkylcarbonyl and m represents an integer in the range of from 1 to 5, or A 3 represents a moiety of formula --(CH 2 ) m-1 --CH ⁇ C(OR 1 )-- wherein R 1 and m are as defined above;
  • R 2 represents OR 3 wherein R 3 represents hydrogen, alkyl, aryl or aralkyl or R 2 represents an aromatic heterocyclyl group or --NR 4 R 5 wherein R 4 and R 5 each independently represent hydrogen, alkyl or alkylcarbonyl or R 4 and R 5 together with the nitrogen atom to which they are attached form a heterocyclic ring, providing that R 2 represents an aromatic heterocyclyl group only when Y as defined below represents a bond;
  • Y represents C ⁇ O or C ⁇ S or a bond providing that Y represents a bond only when R 2 represents the above mentioned aromatic heterocyclyl group;
  • n an integer in the range of from 2 to 6.
  • Suitable aromatic heterocyclyl groups include substituted or unsubstituted, single or fused ring aromatic heterocyclyl groups comprising up to 4 hetero atoms in each ring selected from oxygen, sulphur or nitrogen.
  • Favoured aromatic heterocyclyl groups include substituted or unsubstituted single ring aromatic heterocyclyl groups having 5 to 7 ring atoms, preferably 5 or 6 ring atoms.
  • the aromatic heterocyclyl group comprises 1, 2 or 3 heteroatoms, especially 1 or 2, selected from oxygen, sulphur or nitrogen.
  • Suitable values for A 1 when it represents a 5-membered aromatic heterocyclyl group include thiazolyl and oxazolyl, especially oxazolyl.
  • Suitable values for A 1 when it represents a 6 membered aromatic heterocyclyl group include pyridyl or pyrimidinyl, especially pyridyl.
  • a 1 represents a moiety of formula (a), (b) or (c): ##STR3## wherein: R 6 and R 7 each independently represents a hydrogen or halogen atom, an alkyl or alkoxy group or a substituted or unsubstituted aryl group or when R 6 and R 7 are each attached to adjacent carbon atoms, then R 6 and R 7 together with the carbon atoms to which they are attached form a benzene ring wherein each carbon atom represented by R 6 and R 7 together is substituted or unsubstituted; and in the moiety of formula (a) X 1 represents oxygen or sulphur.
  • a 1 represents a moiety of the abovedefined formula (a).
  • a 1 represents a moiety of the abovedefined formula (b).
  • a 1 represents a moiety of the abovedefined formula (c).
  • a particular form of moiety (c) is a moiety (c'): ##STR4## wherein R 6 and R 7 are as defined in relation to formula (c).
  • R 6 and R 7 together represent a moiety of formula (d): ##STR5## wherein R 8a and R 8b each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R 8a and R 8b each independently represent hydrogen, halogen, alkyl or alkoxy.
  • R 8a represents hydrogen.
  • R 8b represents hydrogen.
  • R 8a and R 8b both represent hydrogen.
  • R 6 and R 7 each independently represent hydrogen, alkyl or a substituted or unsubstituted phenyl group and more favourably, R 6 and R 7 each independently represent hydrogen, alkyl or phenyl.
  • R 6 and R 7 together represent the moiety of formula (d).
  • R 6 and R 7 both represent hydrogen.
  • Optional substituents for A 2 are selected from the group consisting of: halogen, substituted or unsubstituted alkyl and alkoxy.
  • a 2 represents a moiety of formula (e): ##STR6## wherein R 10 and R 11 each independently represent hydrogen, halogen, substituted or unsubstituted alkyl or alkoxy.
  • R 10 and R 11 each independently represent hydrogen, halogen, alkyl or alkoxy.
  • a suitable alkoxy group is a methoxy group.
  • R 10 and R 11 each represent hydrogen.
  • A3 represents a moiety of formula --(CH 2 ) m --CH(OR 1 )--.
  • a 3 represents a moiety of formula --CH ⁇ C(OR 1 )--.
  • R 1 represents alkyl
  • suitable alkyl groups are C 1-6 alkyl groups, for example methyl, ethyl, propyl, such as n-propyl and iso-propyl, and butyl, such as t-butyl.
  • a preferred alkyl group is an ethyl group.
  • R 1 When R 1 is substituted alkyl, particular substituents for the alkyl group include halo, hydroxy, alkoxy or a moiety --NR s R t , wherein R s and R t each independently represents hydrogen or alkyl or R s and R t together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclic ring, or a moiety of formula --CO X 2 wherein X 2 represents OH, alkoxy or a moiety of the above defined formula --NR s R t .
  • Suitable haloalkyl groups include fluoroalkyl groups, such as trifluoroethyl groups.
  • R 1 is substituted alkyl
  • the substituent is attached to a terminal carbon atom of the alkyl group.
  • suitable alkylcarbonyl groups include C 1-6 alkylcarbonyl groups.
  • R 1 represents aryl
  • suitable aryl groups include phenyl or naphthyl groups.
  • suitable aralkyl groups include phenylalkyl groups for example benzyl and phenylethyl groups.
  • a preferred aralkyl group is a benzyl group.
  • Favoured substituents for any aryl group represented by R 1 includes halo, alkyl and alkoxy groups; examples of such substituents include chloro, methyl and methoxy groups.
  • R 1 represents substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl.
  • R 1 is unsubstituted alkyl or unsubstituted aralkyl.
  • R 2 represents OR 3 .
  • R 3 represents hydrogen or alkyl.
  • R 3 is alkyl
  • examples of R 3 include methyl and ethyl.
  • R 2 is an aromatic heterocyclyl group it is suitably a single ring aromatic heterocyclyl group having 5 ring atoms, which ring atoms comprise nitrogen and optionally 1, 2 or 3 additional hetero atoms; examples include 1,2,4-triazole; 1,2,4-oxadiazole and tetrazolyl; generally the aromatic heterocyclyl group is C-linked.
  • Suitable substituents on the aromatic heterocyclyl group include alkyl, aryl, alkoxy and halo, an example of a substituent is methyl.
  • --NR 4 R 5 or --NR s R t represents a heterocyclic ring
  • favoured heterocyclic rings are saturated or unsaturated, fused or monocyclic heterocyclic rings comprising 5, 6 or 7 ring atoms and optionally comprising 1 or 2 additional heteroatoms, selected from O, S or N, in each ring.
  • Favoured rings are saturated rings.
  • Favoured rings are monocyclic rings.
  • Favoured, additional hetero-atoms are N or O. Examples of such heterocyclic rings include N-pyrrolidinyl, N-piperidinyl and N-morpholinyl.
  • a further example of NR 4 R 5 is NH 2 .
  • R 2 represents NR 4 R 5 .
  • R 2 is OR 3 .
  • R 2 represents OR 3 wherein R 3 represents hydrogen, alkyl, aryl or aralkyl or R 2 represents --NR 4 R 5 , Y is CO or CS; preferably, Y is CO.
  • R 2 is an aromatic heterocyclyl group
  • Y is a bond
  • R represents hydrogen or alkyl.
  • suitable acyl groups include alkylcarbonyl groups, such as acetyl.
  • n 1 or 2.
  • n 1
  • n 2
  • a compound of formula (I), and the pharmaceutically acceptable salts thereof may exist in one of several tautomeric forms, all of which are encompassed by the present invention as individual tautomeric forms or as mixtures thereof.
  • the compounds of formula (I) may contain at least one chiral carbon, and hence they may exist in one or more stereoisomeric forms.
  • a 3 represents a moiety of formula --(CH 2 ) m --CH(OR 1 )--- the CH(OR 1 )-carbon atom is a chiral carbon.
  • a 3 represents a moiety of formula --(CH 2 ) m-1 --CH ⁇ C(OR 1 )-- the compounds of formula (I) exist as geometric isomers.
  • the present invention encompasses all of the isomeric forms of the compounds of formula (I) and the pharmaceutically acceptable salts thereof, whether as individual isomers or as mixtures of isomers, including racemates.
  • Suitable substituents for any heterocyclyl group include up to 4 substituents selected from the group consisting of: alkyl, alkoxy, aryl and halogen or any two substituents on adjacent carbon atoms, together with the carbon atoms to which they are attached, may form an aryl group, preferably a phenylene group, and wherein the carbon atoms of the aryl group represented by the said two substituents may themselves be substituted or unsubstituted.
  • ⁇ aryl ⁇ includes phenyl and naphthyl; any aryl group mentioned herein may be optionally substituted with up to five, preferably up to three, groups selected from halogen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, nitro, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, or alkylcarbonyl groups.
  • ⁇ halogen ⁇ refers to fluorine, chlorine, bromine and iodine; preferably chlorine.
  • alkyl groups having straight or branched carbon chains, containing up to 12 carbon atoms.
  • suitable alkyl groups are C 1-12 alkyl groups, especially C 1-6 alkyl groups e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl groups.
  • Suitable substituents for any alkyl group include those indicated above in relation to the term "aryl”.
  • Favoured aralkyl groups are phenylalkyl groups, optionally substituted on the aryl or alkyl moieties as defined herein.
  • Suitable acyl groups include alkylcarbonyl groups
  • Suitable pharmaceutically acceptable salts include salts of carboxy groups and acid addition salts.
  • Suitable pharmaceutically acceptable salts of carboxy groups include metal salts, such as for example aluminium, alkali metal salts such as lithium, sodium or potassium, alkaline earth metal salts such as calcium or magnesium and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine, cycloalkylamines such as bicyclohexylamine, or with procaine, dibenzylpiperidine, N-benzyl- ⁇ phenethylamine, dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine, N-methylglucamine or bases of the pyridine type such as pyridine, collidine, quinine or quinoline.
  • metal salts such as for example aluminium, alkali metal salts such as lithium, sodium
  • Suitable acid addition salts include pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, ⁇ -keto glutarate and ⁇ -glycerophosphate.
  • pharmaceutically acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide
  • pharmaceutically acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphonate, ⁇ -keto glutarate and ⁇ -glycerophosphate.
  • Suitable pharmaceutically acceptable solvates include hydrates.
  • salts and/or solvates of the compounds of formula (I) may be prepared and isolated according to conventional procedures for example sodium salts may be prepared by using sodium methoxide in methanol.
  • the present invention also provides a process for the preparation of a compound of formula (I), or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable hydrate thereof, which process comprises reacting a compound of formula (II):
  • a 3' represents a moiety of formula --(CH 2 ) m --CH(OR 1' )-- wherein R 1' represents R 1 as defined in relation to formula (I) or a protected form thereof, and m is as defined in relation to formula (I), or A 3 represents a moiety of formula --(CH 2 ) m-1 --CH ⁇ C(OR 1' )-- wherein R 1 is as defined above;
  • R 2' represents R 2 as defined in relation to formula (I) or a protected form thereof and R a is a moiety convertible to a moiety of formula (f):
  • a 1 , X and n are as defined in relation to formula (I); with an appropriate reagent capable of converting R a to the said moiety (f) and thereafter, if required, carrying out one or more of the following optional steps:
  • R a represents HX--(CH 2 ) n --O-- wherein X and n are as defined in relation to formula (I), or R a represents OH.
  • R a represents OH.
  • an appropriate reagent capable of converting R a to a moiety (f) is a compound of formula (III):
  • a 1 is as defined in relation to formula (I) and R x represents a leaving group.
  • a suitable leaving group R x includes a halogen atom, preferably a chlorine or bromine atom, or a thioalkyl group for example a thiomethyl group.
  • R 1' is R 1 .
  • R 2' represents OR 3' wherein R 3' represents hydrogen, alkyl, aryl, aralkyl or R 2' represents the above defined moiety --NR 4 R 5 .
  • an appropriate reagent is a compound of formula (IIIA):
  • a 1 , X and n are as defined in relation to formula (I) and R y represents a leaving group, such as a tosylate or mesylate group.
  • reaction between the compound of formula (II) and the appropriate reagent may be carried out under conditions suitable to the particular compound of formula (II) and the reagent chosen:
  • a compound of formula (II) wherein R a represents HX--(CH 2 ) n --O-- and the compound of formula (III) may be carried out in any suitable solvent, for example dimethylformamide, at a temperature which provides a suitable rate of formation of the compound of formula (I), for example at an elevated temperature in the range from 50° C. to 120° C., preferably in the presence of a base such as triethylamine.
  • reaction between the compound of formula (II) wherein R a is OH and the reagent of the abovedefined formula (IIIA) may be carried out in an aprotic solvent, such as dimethylformamide, at a low to an elevated temperature, for example in the range from 50° C. to 120° C., for example at 80° C., and preferably in the presence of a base, such as sodium hydride.
  • an aprotic solvent such as dimethylformamide
  • R y in the compound of formula (IIIA) represents H and R a is OH in the compound of formula (II)
  • a suitable reagent is provided by diethylazodicarboxylate and triphenylphosphine; the coupling reaction may be carried out in any suitable solvent at a low to medium temperature, for example in tetrahydrofuran at a temperature in the range of between 0 and 60° C.
  • a compound of formula (II), wherein A 3' represents a moiety of formula --(CH 2 ) m --CH(OR 1' )--, may be prepared by reacting a source of a carbene of formula (IV):
  • R b is a moiety R a or a moiety convertible to a moiety R a and R 9 is the above defined R 2' or a protecting group, with a compound of formula (V):
  • R 1' is defined in relation to formula (II); and thereafter, if required, converting a moiety R b into a moiety R a and removing any protecting group.
  • Y is CO.
  • R 9 is OR 3' or --NR 4 R 5 .
  • a suitable source of the carbene of formula (IV) is provided by reacting a compound of formula (IVA): ##STR7## wherein A 2 , R 9 , R b , Y and m are as defined in relation to formula (IV), with a rhodium (II) salt, such as rhodium (II) acetate.
  • the reaction between the carbene of formula (IV) and the compound of formula (V) may be carried out under conventional conditions, generally in an inert solvent, such as benzene, or when practicable in compound (V) as solvent, at any temperature providing a convenient rate of formation of the required product, generally at an elevated temperature, such as the reflux temperature of the solvent:
  • an inert solvent such as benzene
  • compound (V) as solvent at any temperature providing a convenient rate of formation of the required product, generally at an elevated temperature, such as the reflux temperature of the solvent:
  • the conditions used are analogous to those disclosed in Tetrahedron Lett., 1973, 2233.
  • the compound of formula (IVA) may be prepared by diazotizing a compound of formula (VI): ##STR8## wherein A 2 , R 9 , R b , Y and m are as defined in relation to the compound of formula (IV), with an appropriate diazotizing agent; and thereafter, if required, converting a moiety R b into a moiety R a and removing any protecting group.
  • a suitable diazotizing agent is an all nitrite, such as iso-amyl nitrite.
  • Suitable diazotising conditions for preparing the compound of formula (IVA) are conventional conditions, for example those disclosed in Tetrahedron Lett., 1971, 4495.
  • Any moiety R b may be converted into a moiety R a by the appropriate conventional means, for example when R b represents --OH and R a represents HX--(CH 2 ) n --O-- the appropriate conversion may be carried out by coupling a compound of formula (VI) wherein R b is OH with a compound of formula (g):
  • the last abovementioned reaction is generally carried out in the presence of a suitable coupling agent; a suitable coupling agent being diethylazodicarboxylate and triphenylphosphine.
  • a suitable coupling agent being diethylazodicarboxylate and triphenylphosphine.
  • the coupling reaction may be carried out in any suitable solvent at a low to medium temperature, for example in tetrahydrofuran at a temperature in the range of between 0 and 60° C.
  • R b in (IV) is either OH or a protected OH, such as a benzylated OH.
  • the compounds of formula (V) are known commercially available compounds or they may be prepared using methods analogous to those used to prepare such compounds.
  • the compounds of formula (VI) are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example those disclosed in Tetrahedron Lett., 1971, 4495, in particular the compound wherein R 9 is OCH 3 , m is 1, A 2 is 1,4-phenylene and R b is OH is a commercially available compound.
  • the compounds of formula (g) are known compounds or they may be prepared using methods analogous to those used to prepare known compounds, for example those disclosed in EP0356214.
  • a compound of formula (I), wherein A 3 represents a moiety of formula --(CH 2 ) m --CH(OR 1 )--, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be prepared by reacting an activated form of a compound of formula (VII): ##STR9## wherein A 1 , A 2 , X, Y, m and n are as defined in relation to formula (II) and R 9 is as defined in relation to formula (IV) with a compound of formula (VIII);
  • R 1 is as defined in relation to formula (I) and L 1 represents a leaving group or atom; and thereafter if required carrying out one or more of the following optional steps:
  • L 1 is a halogen atom, for example a bromine atom.
  • a suitable activated form of a compound of formula (VII) is an anionic form such as a salted form and especially an alkali metal salted form, for example a sodium salt.
  • the activated form of the compound of formula (VII) may be prepared by any appropriate conventional procedure.
  • the anionic form of the compound of formula (VII) may be prepared by treating the compound of formula (VII) with a base, such as a metal hydride base, for example sodium hydride.
  • reaction conditions for the reaction between the compounds of formulae (VII) and (VIII) are generally conventional alkylation conditions.
  • the reaction between the salted form of a compound of formula (VII) and a compound of formula (VIII) may be carried out in an aprotic solvent, such as dimethylformamide, at any temperature providing a suitable rate of formation of the required product, generally an elevated temperature such as in the range of 40° C. to 100° C., for example 80° C.
  • the formation of the activated form of (VII) from (VII)--for example the formation of a salted form of (VII)-- may be carried out in-situ prior to the reaction of the activated form of (VII) with the above defined compound of formula (VIII).
  • a compound of formula (VII) may be prepared by reacting a compound of formula (IX): ##STR10## wherein R a , R 9 , A 2 , Y and m are as defined above and T is hydrogen or a hydroxyl protecting group, with an appropriate reagent capable of converting R a to a moiety of the above defined formula (f).
  • the reagent capable of converting R a to a moiety of formula (f) is as defined above in relation to the formation of a compound of formula (I) from a compound of formula (II).
  • Suitable values for R a include those described hereinbefore.
  • Suitable reaction conditions for the reaction of the compound of formula (IX) and the appropriate reagent include those described above in relation to the preparation of compound (II) with the said appropriate reagent.
  • R a represents a hydroxyl group and a particularly appropriate reagent is the above defined compound of formula (IIIA).
  • reaction between the compound of formula (IX), wherein R a is an hydroxyl group, and the reagent of the abovedefined formula (IIIA) may be carried out in an aprotic solvent, such as dimethylformamide, at a low to an elevated temperature, for example in the range of from 50° C. to 120° C., for example at 80° C., and preferably in the presence of a base, such as sodium hydride.
  • an aprotic solvent such as dimethylformamide
  • the compounds of formula (IX), wherein R a is OH are known compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in Dictionary of Organic Compounds 5th Edition, Vol. 3, p.3222, Chapman & Hall, or D. H. Williams et. al. J. Chem. Soc., Section B, 1969,439, or J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience or for example those disclosed in International Application, Publication No. WO92/02520.
  • a compound of formula (I), wherein A 3 represents a moiety of formula --(CH 2 ) m --CH(OR 1 )--, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be prepared by reacting a source of a carbene of formula (X):
  • a 1 , A 2 , X, Y, m and n are as defined in relation to formula (I) and R 9 is as defined in relation to formula (IV), with a compound of the above defined formula (V); and thereafter, if required, carrying out one or more of the following optional steps:
  • a suitable source of a carbene of formula (X) is provided be reacting a compound of formula (XI): ##STR11## wherein A 1 , A 2 , R 9 , X, Y, m and n are as defined in relation to formula (X) with a rhodium(II) salt, such as a rhodium (II) acetate.
  • the carbene of formula (X) may be prepared from the compound of formula (XI) by using an analogous procedure to that used for the preparation of the carbene of formula (IV) from the compound of formula (IVA).
  • reaction conditions for the reaction between the compounds of formulae (X) and (V) are equivalent to those used in the reaction between the compounds of formulae (IV) and (V).
  • the compound of formula (XI) may be prepared by reaction between the compounds of formulae (IIIA) and (VI) using an analogous procedure to that used for the preparation of the compound of formula (I) from the compounds of formulae (II) and (IIIA) and thereafter diazotized as described above for the conversion of (VI) to (IVA).
  • a compound of formula (I) wherein A 3 represents a moiety of formula --(CH 2 ) m-1 --CH ⁇ C(OR 1 )-- or --(CH 2 ) m --CH(OR 1 )--, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be prepared by reacting a compound of formula (XII):
  • a 1 , A 2 , X, m and n are as defined in relation to formula (I), with a reagent capable of converting the CHO carbon atom into a group of the above defined formula CH ⁇ C(OR 1 )--Y.R 2 ; and thereafter, if required, reducing the group --CH ⁇ C(OR 1 )-- to provide a compound wherein A 3 represents a moiety of formula --(CH 2 ) m --CHOR 1 -- and thereafter, if required, carrying out one or more of the following optional steps:
  • a suitable reagent capable of converting the CHO carbon atom into a group of the above defined formula --CH ⁇ C(OR 1 )--Y.R 2 is a Wittig reagent or preferably a Wadsworth Emmons reagent of formula (XIII): ##STR12## wherein R 1' , R 2' and Y are as defined in relation to formula (II) and R 10 represents a C 1-6 alkyl group, preferably a methyl or ethyl group.
  • the reaction between the compounds of formulae (XII) and (XIII) may be carried out under conventional Wadsworth Emmons reaction conditions, for example in an aprotic solvent, such as tetrahydrofuran, at low to ambient temperature, such as in the range of from 0° to 25° C., conveniently at ambient temperature, preferably in an inert atmosphere and under anhydrous conditions.
  • an aprotic solvent such as tetrahydrofuran
  • ambient temperature such as in the range of from 0° to 25° C.
  • ambient temperature such as in the range of from 0° to 25° C.
  • the compound of formula (XIII) is suitably activated, for example by the addition of a base such as sodium hydride or n-butyl lithium, prior to the addition of the compound of formula (XII).
  • the reduction of a compound wherein A 3 represents a moiety of formula --(CH 2 ) m-1 --CH ⁇ C(OR 1 )-- to provide a compound wherein A 3 represents a moiety of formula --(CH 2 ) m --CH(OR 1 )-- may be carried out using conventional reduction methods, such as catalytic reduction using for example a 10% palladium-on-carbon catalyst in an alkanolic solvent such as ethanol, or by use of a metal/solvent system such as magnesium metal/methanol as described in Tet. Lett. 1986, 27, 2409.
  • a compound of formula (XII) may be prepared from a compound of formula (XIIA):
  • a 1 , A 2 , X, m and n are as defined in relation to formula (I) and R a represents hydrogen or a C 1-6 alkyl group, suitably a methyl group, by conventional methods for converting an ester group into a carbonyl group; one convenient method involves reducing the ester group to give a primary alcohol using for example a metal hydride reducing agent such as lithium aluminium hydride in tetrahydrofuran, and thereafter oxidising the primary alcohol to give the required carbonyl group by use of an oxidising reagent such as pyridine-sulphur trioxide complex in dimethylsulphoxide.
  • a metal hydride reducing agent such as lithium aluminium hydride in tetrahydrofuran
  • a compound of formula (XIIA) may be prepared from a compound of formula (XIIB):
  • reaction conditions for the reaction between the compounds of formulae (IIIA) and (XIIB) are those described above for the reaction between the compounds of formulae (II) and (IIIA).
  • a compound of formula (II) wherein A 3' represents a moiety of formula --CH ⁇ C(OR 1' )-- or --CH 2 --CH(OR 1' )--, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may be prepared by reacting a compound of formula (XIV):
  • R b and A 2 are as defined in relation to formula (IV), with a reagent capable of converting the CHO carbon atom into a group of the above defined formula --CH ⁇ C(OR 1' )--Y.R 2' ; and thereafter, if required, reducing the group --CH ⁇ C(OR 1' )-- to provide a group of formula --CH 2 --CHOR 1' --; and thereafter, if required, removing any protecting group.
  • R b is a protected OH group.
  • a suitable reagent capable of converting the CHO carbon atom of compound (XIV) into a group of the above defined formula --CH ⁇ C(OR 1' )--Y.R 2' is a compound of the above defined formula (XIII) in optionally protected form as defined by the nature of R 1' and R 2' in the required compound of formula (II).
  • Suitable conditions for the reaction between the compound of formula (XIV) and the said reagent are analogous to those described above for the reaction between the compounds of formulae (XII) and (XIII).
  • the compounds of formula (XIIB) are known commercially available compounds or they are compounds prepared by analogous methods used to prepare such compounds or they may be prepared from such compounds, for example by converting a commercially available carboxylic acid into an alkyl ester.
  • the compounds of formula (XIII), are known compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in Annalen Chemie 1966, 699, 53 or J. Org. Chem. 1983, 48, 3408.
  • the compounds of formulae (XIV) are known compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in EP 0306228.
  • a compound of formula (I), wherein A 3 represents a moiety of formula --CH 2 --CH(OR 1 )-- wherein R 1 represents alkyl, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, may also be prepared by hydrolysing a compound of formula (XV):
  • a 1 , A 2 , R 1 , X and n are as defined in relation to formula (I) to provide a compound of formula (I) wherein R 2 represents OH; and thereafter, if required, converting R 2 as OH into another R 2 ; and thereafter, if required, carrying out one or more of the following optional steps:
  • the hydrolysis of the compound of formula (XV) may be carried out using conventional conditions and reagents for nitrile hydrolysis, for example basic hydrolysis using 10% sodium hydroxide in methanol.
  • R 2 as OH into another R 2 may be effected by using any convenient method, such as those methods described hereinafter.
  • a compound of formula (XV) may be prepared from a compound of formula (XVI):
  • reaction between the compounds of formulae (XVI) and trimethylsilylcyanide may be carried out in an inert solvent, such as dichloromethane, at low to ambient temperature, conveniently at ambient temperature and preferably in the presence of a Lewis acid catalyst, such as boron trifluoride etherate.
  • an inert solvent such as dichloromethane
  • a Lewis acid catalyst such as boron trifluoride etherate.
  • a compound of formula (XVI) may be prepared from a compound of formula (XVII):
  • R 1a is as defined above.
  • reaction between the compounds of formulae (XVII) and (XVIII) is suitably carried out using the compound of formula (XVIII) as solvent, generally at an elevated temperature such as the reflux temperature of the solvent and preferably in the presence of p-toluenesulphonic acid.
  • R 1a is methyl
  • a compound of formula (XVII) may be prepared by reaction of the above defined compound of formula (XII), wherein m is 1, with a reagent capable of converting the CHO carbon atom of formula (XII) into a group of the above defined formula --CH ⁇ CH--OR 1 , the reagent being suitably a Wittig reagent of formula (XIX):
  • R 1 is as defined in relation to formula (I).
  • the reaction between the compounds of formulae (XII) and (XIX) may be carried out under conventional Wittig reaction conditions, for example in an aprotic solvent, such as tetrahydrofuran, at low to ambient temperature, such as in the range of from -10° to 25° C., conveniently at ambient temperature and, preferably, in an inert atmosphere under anhydrous conditions.
  • an aprotic solvent such as tetrahydrofuran
  • ambient temperature such as in the range of from -10° to 25° C.
  • ambient temperature such as in the range of from -10° to 25° C.
  • the compound of formula (XIX) is suitably activated by, for example, the addition of a base such as sodium hydride, n-butyl lithium or lithium diisopropylamide, prior to the addition of the compound of formula (XII).
  • the compounds of formula (XVIII) and (XIX) are known compounds or they are compounds prepared by methods analogous to those used to prepare known compounds, for example those disclosed in J. March, Advanced Organic Chemistry, 3rd Edition (1985), Wiley Interscience.
  • a compound of formula (I), wherein A 3 is (CH 2 ) m --CH(OR 1 )-- and R 2 is a C-linked aromatic heterocyclyl group, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable hydrate thereof, may be prepared by reacting a compound of the above defined formula (XII) with an activated form of a compound of formula (XX) ##STR13## wherein het-CH is an aromatic heterocyclic group represented by R 2 which contains at least 1 carbon atom and thereafter converting the compound wherein R 1 is hydrogen into another R 1 ; and thereafter if required:
  • a suitable activated form of a compound of formula (XX) is a salted form such as a lithium salted form.
  • the activated form of a compound of formula (XX) may be prepared by reacting an aromatic heterocyclic group Het-CH or Het-CL, wherein L is a leaving group such as halogen, with an appropriate, conventional activating agent such as a salting agent, for example an alkyl lithium, in an aprotic solvent such as tetrahydrofuran according to known methods and procedures for example those disclosed in Adv. Heterocyclic chem., 1993, 56, 155.
  • the compound of formula (XXI) may be prepared by dehydrating a compound of formula (I) wherein A 3 is (CH 2 ) m --CH(OR 1 ) and YR 2 is CONH 2 using for example POCl 3 .
  • reaction between the compound of formula (XXI) and the source of azide ions may be carried out under conventional conditions for example when sodium azide is the source of azide ions the reaction may be effected in an aprotic solvent such as dimethylformamide generally at an elevated temperature, for example the reflux temperature of the solvent; preferably in the presence of trimethylsilyl chloride.
  • an aprotic solvent such as dimethylformamide generally at an elevated temperature, for example the reflux temperature of the solvent; preferably in the presence of trimethylsilyl chloride.
  • Suitable conversions of one group R into another group R include converting a group R which represents hydrogen into a group R which represents an acyl group; such conversion may be carried out using an appropriate conventional acylation procedure, for example treating an appropriately protected compound of formula (I) with an acylating agent.
  • acetic anhydride may be used to prepare the compound of formula (I) wherein R is acetyl.
  • Suitable conversations of one group OR 1 into another group OR 1 include the conversion of one substituent into another substituent when R 1 represents substituted alkyl, for example the reduction of a CO 2 R u substituent, wherein R u is C 1-6 alkyl, to provide a CH 2 OH substituent.
  • the above mentioned reduction may be carried out using any conventional reduction method, for example using boronhydride reducing agents such as sodium borohydride in a solvent such as methanol.
  • Suitable conversions of one group Y.R 2 wherein Y is CO into another group Y.R 2 include:
  • Suitable hydrolysis methods for use in conversion c(i) are conventional ester hydrolysis methods, for example using an alkali hydroxide in aqueous methanol.
  • Suitable amination methods for conversion c(ii) or c(iii) include conventional methods, for example treatment with aqueous ammonia in tetrahydrofuran/methanol.
  • alkyl esters may be prepared by using the appropriate alkanol, for example methanol, in the presence of an acid and aralkyl esters may be prepared by treatment of a salted YOH group, such as a sodium salt, with an appropriate aralkyl halide, for example benzyl bromide.
  • a salted YOH group such as a sodium salt
  • Suitable conversion of a group Y.NH 2 wherein Y is CO into a group Y--C-Het wherein Y is a bond and C-Het is a C-linked aromatic heterocyclyl group includes:
  • a) reaction with a hydrazine for example hydrazine hydrate, and an amide acetal, such as dimethylformamide dimethyl acetal, to provide a 1,2,4-triazole; or
  • a hydroxylamine for example hydroxylamine hydrochloride
  • an amide acetal such as dimethylformamide dimethyl acetal
  • Suitable conversions of one group CO.R 2 into another group CS.R 2 may be effected using conventional methods, for example by using Lawesson's reagent in a solvent such as toluene, at any temperature providing an acceptable rate of formation of the required product, conveniently at the reflux temperature of the solvent.
  • Suitable reductions of one group --CH ⁇ C(OR 1 )-- to a group --CH 2 CH(OR 1 )-- may be carried out using any convenient reduction procedure, such as the catalytic reduction or metal/solvent reduction methods as described hereinbefore.
  • any reactive group in the substrate molecule may be protected, according to conventional chemical practice.
  • Suitable protecting groups in any of the abovementioned reactions are those used conventionally in the art.
  • suitable hydroxyl protecting groups include benzyl or trialkylsilyl groups.
  • benzyloxy group may be prepared by treatment of the appropriate compound with a benzyl halide, such as benzyl bromide, and thereafter, if required, the benzyl group may be conveniently removed using catalytic hydrogenation or a mild ether cleavage reagent such as trimethylsilyl iodide or boron tribromide.
  • a benzyl halide such as benzyl bromide
  • the present invention provides a process for separating optical isomers of a compound (the substrate ester) which comprises a moiety of formula (H): ##STR15## wherein C* is a chiral carbon, Z is a C 1-12 alkyl group and Z 1 is a C 1-12 alkyl, aryl or an aryl C 1-12 alkyl group, which process comprises enantioselectively hydrolysing the ester group CO 2 Z of one enantiomer into a carboxyl group with a lipase from Rhizopus delemar, Rhizopus arrhizus, Rhizopus LIP F4 or a lipase from Mucor miehei; and thereafter, as necessary, isolating either the enantiomerically enriched product carboxylic acid or the enanatiomerically enriched substrate ester.
  • C* is a chiral carbon
  • Z is a C 1-12 alkyl group
  • Z 1 is a C 1-12 alkyl,
  • the enantiomerically enriched product carboxylic acid and/or the enanatiomerically enriched substrate ester may be isolated using conventional extraction methods, such as phase separation and/or extraction into a suitable solvent, and thereafter, if required it may be chromatographed.
  • the enantiomerically enriched substrate ester may be converted by hydrolysis into the respective carboxylic acid which may then be isolated in the usual way.
  • the enantiomerically enriched substrate ester may be hydrolysed by treatment with the abovementioned lipases to give the respective carboxylic acid.
  • the compounds of formula (I) which fall within formula (H) are those compounds wherein Z represents R 3 and Z 1 represents R 1 :
  • the novel process may be used to prepare enantiomerically enriched compounds of formula (I) wherein A 3 represents (CH 2 ) m --CH(OR 1 )--, Y represents CO, R 2 is OR 3 and A 1 , A 2 , R 1 , R 3 X, m and n are as defined in relation to formula (I)--(hereinafter referred to as compounds of formula (IA)).
  • the microbial lipase enzymes may be obtained by conventional culturing techniques such as those disclosed in J. Bacteriol., 1982, Vol.150 498-505. H. Gilbert and M. Tully, European Patent Application No. 0198440 and British Patent No. 1,474,519.
  • the lipase may be isolated as a pure enzyme or, in the alternative a suitable source of the lipase may be incorporated into the reaction.
  • the microbial lipase enzymes are obtained commercially as purified or partially purified enzyme preparations.
  • the hydrolysis of the compound of formula (H) may be carried out in any suitable aqueous solvent having controlled pH, for example in an aqueous buffer or in a solvent wherein the pH is controlled by the addition of aqueous sodium hydroxide, at a pH which provides a suitable rate of formation of the required product, which is generally a pH in the range of from 5 to 9, such as in the range of from 6 to 8, for example at pH7.
  • the hydrolysis may be carried out at any temperature which provides a suitable rate of formation of the required product, being generally at a low to ambient temperature, such as a temperature in the range of from 5° C. to 40° C., such as in the range of from 20° C. to 40 ° C. and preferably in the range of from 20° C. to 30° C., for example 23° C.
  • the substrate mixture is introduced into the reaction system as a solution in an organic solvent which may be a water miscible solvent such as acetone, tetrahydrofuran, dimethylsulphoxide, dimethylformamide or acetonitrile.
  • organic solvent which may be a water miscible solvent such as acetone, tetrahydrofuran, dimethylsulphoxide, dimethylformamide or acetonitrile.
  • reaction conditions such as the particular acidic pH and the reaction temperature which provide optimum enrichment for any particular enantiomerically enriched compound (H) may be determined by routine experimentation.
  • the stereoselective reaction provides enantiomerically enriched compound (IA) in the form wherein the required enantiomer is present in greater than 70% w/w; and favourably greater than 80% w/w.
  • the product from the stereoselective process provides enantiomerically enriched compound (IA) in the form wherein the required enantiomer is present as 80-100% w/w, preferably 90-100%, such as 90-95%, and most preferably 95-100%, for example 95%, 96%, 97%, 98%, 99% or 100% w/w.
  • the above mentioned enantiomerically enriched compound (IA) is considered to form a further aspect of the present invention. Accordingly the present invention provides enantiomerically enriched compound (IA) or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof.
  • the present invention provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment of and/or prophylaxis of hyperglycaemia.
  • the present invention also provides a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for use in the treatment and/or prophylaxis of hyperlipidaemia.
  • Cardiovascular disease includes in particular atherosclerosis.
  • ⁇ pharmaceutically acceptable ⁇ embraces compounds, compositions and ingredients for both human and veterinary use: for example the term ⁇ pharmaceutically acceptable salt ⁇ embraces a veterinarily acceptable salt.
  • composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
  • compositions of the present invention will be adapted for oral administration, although compositions for administration by other routes, such as by injection and percutaneous absorption are also envisaged.
  • the carrier may comprise a diluent, filler, disintegrant, wetting agent, lubricant, colourant, flavourant or other conventional adjuvant.
  • Typical carriers include, for example, microcrystalline cellulose, starch, sodium starch glycollate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, magnesium stearate or sodium lauryl sulphate.
  • the compound of the general formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof may be taken in doses, such as those described above, one to six times a day in a manner such that the total daily dose for a 70 kg adult will generally be in the range of from 0.1 to 6000 mg, and more usually about 1 to 1500 mg.
  • the active ingredient may be administered by mouth, usually once or twice a day and in an amount in the range of from about 0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg. Similar dosage regimens are suitable for the treatment and/or prophylaxis of hyperlipidaemia in non-human mammals.
  • the dosages regimens for the treatment of hypertension, cardiovascular disease and eating disorders will generally be those mentioned above in relation to hyperglycaemia.
  • the present invention provides the use of a compound of formula (I), or a tautomeric form thereof and/or a pharmaceutically acceptable salt thereof and/or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of hyperglycaemia.
  • the title compound a 1:1 mixture of double bond isomers, was prepared from triethyl 2-(4methylphenoxy)phosphonoacetate by a method analogous to that described for Example 6, and was obtained as a gum.
  • reaction mixture was immersed in a cold water bath and stirring continued until all the metal had dissolved ( ⁇ 4 hrs), then the mixture was evaporated in vacuo. The residue was suspended in water (100 mL) and stirred vigorously during the addition of concentrated hydrochloric acid, to give (once all the suspension had dissolved) a final pH of 1.5.
  • the title compound a foam, was prepared from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-(phenylmethoxy)propanoate by a procedure analogous to that described for Example 2. This material was used directly in the salt forming step without further purification.
  • the title compound a gum, was prepared from 4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenylethanal by a method analogous to that described for Example 6, and was isolated as a 1:1 mixture of double bond isomers.
  • the title compound a gum, was prepared from ethyl (E/Z)-4-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxybut-2-enoate by a method similar to that described for Example 8, using ethanol as solvent.
  • Triethyl 2-ethoxyphosphonoacetate (3.44 g) was dissolved in dry tetrahydrofuran (25 mL) and the solution added slowly to an ice-cooled, stirred suspension of sodium hydride (60% dispersion in mineral oil; 0.56 g) in tetrahydrofuran under an argon atmosphere. The mixture was stirred at 0° C. for 30 minutes prior to the addition of a solution of 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzaldehyde (Eur. Patent Appl. Publication Number EP 0306228) (3.29 g) in tetrahydrofuran (30 mL).
  • the basic aqueous extract was acidified by the addition of hydrochloric acid and re-extracted into dichloromethane to yield, after drying and evaporation, 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-methoxypropanoic acid as a white solid.
  • the title compound a gum, was prepared from ethyl (E/Z)-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-tert-butoxypropenoate by a method analogous to that described for Example 25. This material was contaminated with some of the corresponding methyl ester and the mixture was used directly in the next stage without further purification.
  • the benzene solution was dried (MgSO 4 ) and evaporated and the residual oil chromatographed twice on silica gel, firstly with 20% ethyl acetate in hexane as eluent and subsequently with 4% ethyl acetate in dichloromethane as eluent to afford the title compound as an oil.

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NO990227L (no) 1995-03-02
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CN1042532C (zh) 1999-03-17
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US5869495A (en) 1999-02-09
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MX9303981A (es) 1994-04-29
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FI950016A0 (fi) 1995-01-02
DE69331010D1 (de) 2001-11-29
CA2139442A1 (en) 1994-01-20
SK695A3 (en) 1995-07-11
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NO305318B1 (no) 1999-05-10
CN1215724A (zh) 1999-05-05
EP0648212B1 (en) 2001-10-24
NO950009D0 (no) 1995-01-02

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